Pyridyl-{62 -hydroxysulfoxides and sulfones and derivatives

ABSTRACT

The present invention relates to pyridyl- Beta -hydroxy sulfoxides and sulfones having structural formulas:   WHEREIN R1 and R2 are hydrogen, lower alkyl, cycloalkyl, lower alkenyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocyclic, substituted heterocyclic, acyl, halogen, lower alkoxy, nitro, mercapto, lower alkylthio, hydroxy, amino, lower alkylamino, dilower alkylamino and the like. R3 and R4 are hydrogen, lower alkyl or aryl. R5 is alkyl up to 12 carbon atoms, aryl, substituted aryl, heterocyclic or substituted heterocyclic. R6 is alkyl of up to 12 carbon atoms or acyl When R6 is hydrogen these compounds are prepared by treating a di alkylsulfoxide or sulfone with a pyridine aldehyde. They can also be prepared by reducing a pyridyl- Beta -ketosulfoxide, or sulfone, with an alkali metal borohydride. These compounds are useful as immunosuppressive agents.

United States Patent [191 Morrison et al.

PYRIDYL-B-HYDROXYSULFOXIDES v AND SULFONES AND DERIVATIVES Inventors:Glenn C. Morrison, Dover; John Shavel, Jr., Mendham; Wiaczeslaw Cetenko,Parsippany, all of NJ.

Warner-Lambert Company, Morris Plains, NJ.

Filed: Sept. 28, 1970 Appl. No.: 76,288

Assignee:

US. Cl. ..260/294.8 F, 260/2948 G, 424/263 Int. Cl. ..C07d 31/50 Fieldof Search ..260/294.8 F

[56] References Cited OTHER PUBLICATIONS Science News, Vol. 94, page319, Sept. 28, 1968.

Science News, Vol. 95, pages 457-458, May 10, 1969.

The present invention relates to pyridyl-B-hydroxy sul- 3,725,420 Apr.3, 1973 wherein R and R are hydrogen, lower alkyl, cycloalkyl, loweralkenyl, aryl, substituted aryl, aralkyl, substituted aralkyl,heterocyclic, substituted heterocyclic, acyl, halogen, lower alkoxy,nitro, mercapto, lower alkylthio, hydroxy, amino, lower alkylamino,dilower alkylamino and the like. R and R are hydrogen, lower alkyl oraryl. R is alkyl up to 12 carbon atoms, aryl, substituted aryl,heterocyclic or substituted heterocyclic. R is alkyl of up to 12 carbonatoms or acyl When R is hydrogen these compounds are prepared bytreating a di alkylsulfoxide or sulfone with a pyridine aldehyde Theycan also be prepared by reducing a pyridyl-B-ketosulfoxide, or sulfone,with an alkali metal borohydride. These compounds are useful asimmunosuppressive agents.

' 5 Claims, No Drawings PYRIDYL-B-HYDROXYSULFOXIDES AND SULFONES ANDDERIVATIVES The present invention relates to pyridyl-B-hydroxysulfoxides and sulfones having the following structural formulas:

on, It, 9R. Flt; 0n( J-s-R err-p-s-n.

| R. )N R4 0 2 R2 wherein R and R are hydrogen,.lower alkyl, cycloalkyl,lower alkenyl, aryl, substituted aryl, aralkyl, substituted aralkyl,heterocyclic, substituted heterocyclic, acyl, halogen, lower alkoxy,nitro, mercapt'o, lower alkylthio, hydroxy, amino, lower alkylamino,dilower alkylamino and the like. R and R are hydrogen, lower alkyl oraryl. R is alkyl up to 12 carbon atoms, aryl, substituted aryl,heterocyclic or substituted heterocyclic. R is alkyl of up to l2carbonatoms or acyl.

As used throughout the specification and claims:

The term lower alkyl and the lower alkyl portion of lower alkoxyembraces both straight and branched chain alkyl radicals containing fromone to six carbon atoms, for example, methyl, ethyl, 'propyl, isopropyl,nbutyl, n-amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl, and the like;the term lower alkenyl embraces straight and branched chain alkenylradicals containing.

from two to six carbon atoms, for example, vinyl, ally], l-butenyl,l-hexenyl, 2,3-di-methyl-l-butenyl, 2-ethyll-butenyl and the like; theterm cycloalkyPencompasses saturated monocyclic groups having from threeto eight carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 'cycloheptyl and cyclooctyl;

the term aryl denotes a monocyclic aromatic hydrocarbon of six to eightcarbon atoms, such as phenyl, tolyl and the like; the term aralkylencompasses lower alkyl groups in which aryl as defined above issubstituted for a hydrogen atom, such as for example, benzyl, phenethyland the like; the term substituted arylmeans an aryl as defined above inwhich one ormore of the hydrogen atoms of the aryl portion have beensubstituted bya functional group such as halogen, hydroxyl, lower alkyl,trifluoromethyl, amino, substituted amino, lower alkoxy and the like;the term substituted aralkyl" means those aralkyl groups having furthersubstituents in their ring portions, such as halogen, hydroxyl, loweralkyl, trifluoromethyl; amino,

substituted amino, lower alkoxy and the like; thev termheterocyclic"encompasses those five and six member heterocyclic ringshaving at least one hetero atom in the ring such as nitrogen, oxygen orsulfur, for example, pyridyl, thienyl, furyl and the like; the termsubstituted heterocyclic are those heterocyclic radicalsas defined abovehaving further substituents in their ring portions, for example, bygroups such as hydrogen, halogen lower alkyl and lower alkoxy and thelike; the term acyl means those hydrocarbon carboxylic acids of lessthan 12 carbon atoms, as exemplified by the lower alkanoic acids (e.g.,acetic, propionic, butyric and tert-pentanoic acid), the lower alkanoicacids, the monocyclic aryl carboxylic acids (e.g., benzoic and toluicacids), the monocyclic aryl lower alkanoic acids (e.g., phenacetic andB-phenylpropionic acid), the

macol. 21: 127-136 and BritJJ, Pharmacol. 24:

632640 (1965); the sensitized response to bacterial endotoxin shown inthe spleen-cell assay, Jerne et al., Cell-bound Antibodies, WistarInstitute Press, 1963, p. 109; skin transplant rejection in mice andrats and mammary gland rejection in rats, Billingham, Transplantation ofCells and Tissues, Wistar Institute Press, 1961, p. 1; contact andprotein hypersensitivities in guinea pigs, rabbits and rats, Uhr,Physiol. Rev. 46:

359-419. The compounds of this invention, as well as their correspondingacid addition salts, N-oxides and quaternary ammonium salts, showed, ata dosage range of about 1 to 1,000 mg/kg, typically 25 to mg/kg, threeor four times daily, orally or by injection, depending on the host,effectiveness in suppressing these various expressions of the delayedhypersensitivity immunological response.

As far as toxicity is concerned, these compounds of this invention haveextremely low toxicity, for example, oral administration at a dose of 5g/kg or intravenous injection at a does of 1 g/kg to mice produces nodeaths.

In order to use these compounds, they may be combined with inertpharmaceutical excipients, such as lactose, mannitol, starch, andformulated into dosage forms such as tablets, capsules and the like. Forparenteral administration, these compounds may be formulated with aninert parenterally acceptable vehicle; such as water, saline, sesame oiland the like. These various pharmaceutical dosage forms are compoundedby methods well known to the pharmacists art.

According to the present invention, these compounds of this inventionwherein R is hydrogen, are prepared by two methods. The first methodinvolves treating a dialkyl sulfoxide or sulfone with a pyridine al-These compounds wherein R is alkyl are prepared by treating the abovecompounds wherein R is hydrogen with sodium hydride and an alkyl halide.Those compounds where R, is acyl are prepared by treating thosecompounds wherein R is hydrogen with an acyl halide.

The following Examples are included to further illustrate the practiceof this invention.

EXAMPLE 1 ai-[(Methylsiil firiyl)methyl]-2-pyridinemethanol. Method A Toa solution of 55 g of 2-[(methylsulfinyl)acetyl] pyridine in 1.2 1 ofwater was added a solution of 3.5 g of sodium borohydride in 30 ml ofwater while the temperature was maintained at 2025 with icebath cooling.After the addition had been completed, stirring was continued for 3hours. The reaction mixture was saturated with sodium chloride andextracted with chloroform. The chloroform layer was dried over sodiumsulfate and the solvent was removed. Four recrystallizations of theresidue from ethyl acetate gave 10 g (18 percent of a crystalline solid(Isomer A) mp l11.5-112.5.

Anal. Calcd for c,1-t,,No,s; C, 51.87; H, 5.99; N, 7.56; S, 17.31.Found: C, 51.70; H, 5.91; N, 7.62; S, 17.44.

On concentration of the mother liquor from the second recrystallization,there was deposited a solid, which after three more recrystallizationsfrom ethyl acetate, afforded 3.0 g (5 percent) of a solid (lsomer B) mp74-75.

Anal. Calcd for C H NO S: C, 51.87; H, 5.99; N, 7.56; S, 17.31. Found:C, 51.69; H, 5.95; N, 7.40; S, 17.37.

Method B A mixture of 13.9 g of sodium hydride and 150 ml of dimethylsulfoxide was heated at 72 until hydrogen evolution ceased. A solutionof 32.1 g of picoline aldehyde was added over a 25 min. interval at2025. After the addition had been completed, stirring was continued for2 hours at room temperature. The reaction mixture was poured onto 300 gof ice and the pH' EXAMPLE 2 O CHCHzS C Ha O CH:

2[ 1-Methoxy-2-(methylsulfinyDethyl] pyridine To a suspension of 5.98 gof sodium hydride in 70 ml of dimethyl formamide was added a solution of26.4 g of isomer A of a-[(methylsulfinyl)methyl]-2-pyridinemethanol in100 ml of dimethyl formamide at l5-20. The mixture was stirred at theroom temperature for 35 min. To the resulting solution was added 21.4 gof methyl iodide in 20 ml of dimethyl formamide at l5-20 over a 10 min.interval. After the addition had been completed, stirring was continuedfor an additional 3 hours at room temperature. The reaction mixture waspoured into 400 ml of cold water and extracted with chloroform. Thechloroform solution was dried over sodium sulfate and the solvent wasremoved. The residue was chromatographed on alumina. Elution with ethylacetate gave, after recrystallization from ether, 17 g (62 percent) of asolid mp 65-66.

Anal. Calcd. for C H NO S: C, 54.25; H, 6.58; N, 7.03; S, 16.09. Found:C, 54.09; H, 6.58; N, 7.08; S, 16.16.

Subjection of 16.1 g of isomer B of a[(methylsulf inyl)methyl]-2-pyridinemethanol to the procedure for isomer A gave 18 g of anoil. Chromatography on Silica Gel gave, on elution with chloroform, 13.3g of an oil. To a solution of the base in 1.4 l of ether was added asolution of 9.46 g of perchloric acid in 25 ml of ethanol. There wasdeposited a 17.9 g of a solid mp 164 dec. Recrystallization frommethanol gave an analytical sample mp 164165.

Anal. Calcd. for C H SO 'HCl0 C, 36.07; H, 4.71; N, 4.67; S, 36.07; Cl,11.83. Found: C, 36.10; H, 4.74; S, 10.87; N, 4.85;C1, 11.89.

EXAMPLE 3 pyridine min. under a nitrogen atmosphere. The reaction wasstirred for an additional 30 min. during which it was allowed to warm toambient temperature. The solution was again cooled to 0, and a solutioncontaining 3.79 g of benzoyl chloride in 25 ml of dimethyl formamide wasadded dropwise over a 15 min. interval. The resulting mixture wasallowed to warm to room temperature and to stir for 24 hours. Themixture was poured into ml of ice water and extracted several times withchloroform. The combined organic extracts were dried over anhydroussodium sulfate and the solvent was evaporated in vacuo to afford a darkbrown oil. The oil was trituration with ether, and the resultingcrystals were collected to yield 2.55 g (34 percent) of a solid, mp.l55l56. Three recrystallizations from ethyl acetate gave an analyticalsample, mp. l 61.

Anal. Calcd. for C H, NO S: C, 62.26; H, 5.23; N, 4.84; S, 11.08. Found:C, 62.60; H, 5.19; N, 4.76; 5, 11.13.

2-[ (Methylsulfonyl)methyl1-2-pyridinemethanol To a stirred solution of54.9 g of 2-[ (methylsulfonyl) l0 acetyllpyridine in 2.4 l of 80 percentaqueous methanol cooled to was added in several portions 2.77 g ofsodium borohydride. The temperature rose to l7 during addition. Themixture was stirred at room temperature for 5 hr. and then the methanolwas removed by distillation at reduced pressure. The aqueous residue wasextracted with chloroform. The combined chloroform extracts were driedover sodium sulfate and the solvent was removed by distillation atreduced pressure. There was obtained 50.2 (92 percent) ofa solid.Recrystallization from ethanol gave analytical sample, mp. l5455.

Anal. Calcd for C H NO S: C, 47.75; H, 5.51; N, 6.96; S, 15.93. Found:C, 47.97; H, 5.48; N, 6.87; S, 15.66.

We claim:

1. A member selected from the group consisting of .wherein R and R arehydrogen, R and R are each a compounds of the formulas:

0R9 R3 0R6 R3 (T) H-+H:SRs I (EH-(ES--Rr N R4 N 114 5 R1 and R2 I IImember selected from the group consisting of hydrogen, lower alkyl andphenyl; R is alkyl up to 12 .carbon atoms; R is a member selected fromthe group consisting of alkyl of up to 12 carbon atoms, acyl of a loweralkanoic acid, and benzoyl, and the sulfoxide chain is attached in the aposition of the pyridyl ring; its pharmaceutically acceptable acidaddition salts, and its N-oxide.

2. A compound'according to claim 1 which is a-[(Methylsulfinyl)methylf7-2-pyridinemethanol.

3. A compound according to claim 1 which is 2[l-Methoxy-2-(methylsulfinyl)ethyl] pyridine.

4. A compound according to claim 1 which is 2-[ l-0-Benzoyl-2-(methylsulfinyl)ethyl] pyridine.

5. A compound according to claim 1 which is 2-[(Methylsulfonyl)methylfu-2-pyridinemethanol.

2. A compound according to claim 1 which is Alpha -((Methylsulfinyl)methyl)-2-pyridinemethanol.
 3. A compound according toclaim 1 which is 2( 1-Methoxy-2-(methylsulfinyl)ethyl) pyridine.
 4. Acompound according to claim 1 which is2-(1-0-Benzoyl-2-(methylsulfinyl)ethyl) pyridine.
 5. A compoundaccording to claim 1 which is 2-((Methylsulfonyl)methyl)-2-pyridinemethanol.